3-guanidinocarbonyl-1-heteroaryl-indole derivatives, preparation process, their use as medicaments, and pharmaceutical compositions comprising them

ABSTRACT

The present invention relates to 3-guanidinocarbonyl-1-heteroaryl-indole derivatives, pharmaceutical compositions comprising such derivatives, methods of treatment comprising administering such derivatives, and processes for their preparation.

[0001] The present invention relates to 3-guanidinocarbonyl-1-heteroaryl-indole derivatives of the formula (I)

[0002] in which R1 to R3 and Ar have the meanings stated below. The inventive compounds are suitable for example as antiarrhythmic medicaments with a cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris. They also inhibit in a preventive manner the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias and of heart failure.

[0003] The invention relates to compounds of the formula I, in which

[0004] R1 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

[0005] R2 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH,

[0006] R3 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH,

[0007] Ar is a 9- or a 10-membered bicyclic heteroaryl having one, two or three nitrogen atoms, which may be linked via any of its positions and which is substituted in at least one of its positions by alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, nitro, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O)_(n)R4, CO₂H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO₃H,

[0008] n=0, 1 or 2,

[0009] Ra and Rb are independently of each other hydrogen, linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which may optionally contain another hetero atom chosen from O, S and N,

[0010] R4 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH₂

[0011] and racemic mixtures, enantiomers and diastereomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof.

[0012] Preference is given to compounds of the formula I, in which

[0013] R1 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

[0014] R2 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH,

[0015] R3 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH,

[0016] Ar is quinoline, isoquinoline, quinazoline or 7H-pyrrolo-[2,3-d]-pyrimidine, which may be linked via any of its positions and which is substituted in at least one of its positions by alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, nitro, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O)_(n)R4, CO₂H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO₃H,

[0017] n=0, 1 or 2,

[0018] Ra and Rb

[0019] are independently of each other hydrogen, linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which may optionally contain another hetero atom chosen from O, S and N,

[0020] R4 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH₂

[0021] and racemic mixtures, enantiomers and diastereomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof.

[0022] More preference is given to compounds of the formula I, in which

[0023] R1 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

[0024] R2 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH,

[0025] R3 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH,

[0026] Ar is 4-quinolinyl, 4-quinazolinyl or 4-(7H-pyrrolo-[2,3-d]-pyrimidinyl), which is substituted in at least one of its positions by alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, nitro, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O)_(n)R4, CO₂H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO₃H,

[0027] n=0, 1 or 2,

[0028] Ra and Rb

[0029] are independent of each other hydrogen, linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which may optionally contain another hetero atom chosen from O, S and N,

[0030] R4 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH₂

[0031] and racemic mixtures, enantiomers and diastereomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof.

[0032] In one embodiment compounds of the formula I are defined as above and R1 represents a hydrogen or methyl.

[0033] In another embodiment compounds of the formula I are defined as above and R2 and R3 represent independent of each other hydrogen, methyl or methoxy, preferably R2 hydrogen or methoxy and R3 hydrogen.

[0034] In another embodiment compounds of the formula I are defined as above and Ar is substituted by one or two substituents, preferably one substituent, chosen from the group of methyl, ethyl, F, Cl, Br, methoxy, ethoxy or CF₃, preferably from the group of methyl, F, Cl, methoxy or CF₃.

[0035] Specific preference is given to compounds of the formula I, characterised in that it is chosen from the group of:

[0036] 3-Guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0037] 3-Guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0038] 3-Guanidinocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0039] 3-Guanidinocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0040] 3-Guanidinocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole,

[0041] 3-Guanidinocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole,

[0042] 3-Guanidinocarbonyl-1-(2-methylquinol-4-yl)-1H-indole,

[0043] 3-Guanidinocarbonyl-1-(6-chloroquinol-4-yl)-1H-indole,

[0044] 3-Guanidinocarbonyl-1-(7-chloroquinol-4-yl)-1H-indole,

[0045] 3-Guanidinocarbonyl-1-(8-chloroquinol-4-yl)-1H-indole,

[0046] 3-Guanidinocarbonyl-1-(6-fluoroquinol-4-yl)-1H-indole,

[0047] 3-Guanidinocarbonyl-1-(8-fluoroquinol-4-yl)-1H-indole,

[0048] 3-Guanidinocarbonyl-1-(6,8-difluoroquinol-4-yl)-1H-indole,

[0049] 3-Guanidinocarbonyl-1-(6-fluoro-2-methylquinol-4-yl)-1H-indole,

[0050] 3-Guanidinocarbonyl-1-(7-fluoro-2-methylquinol-4-yl)-1H-indole,

[0051] 3-Guanidinocarbonyl-1-(8-fluoro-2-methylquinol-4-yl)-1H-indole,

[0052] 3-Guanidinocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole,

[0053] 3-Guanidinocarbonyl-1-(7-chloroquinol-4-yl)-5-methoxy-2-methyl-1H-indole,

[0054] 3-Guanidinocarbonyl-1-(6-fluoroquinol-4-yl)-5-methoxy-2-methyl-1H-indole,

[0055] and

[0056] 3-Guanidinocarbonyl-1-(6-chloro-quinazolin-4-yl)-5-methoxy-2-methyl-1H-indole, and tautomers thereof and pharmaceutically acceptable salts thereof, and more particularly the following compounds:

[0057] 3-Guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0058] 3-Guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0059] 3-Guanidinocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0060] 3-Guanidinocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole,

[0061] 3-Guanidinocarbonyl-1-(6-methoxyquinol4-yl)-1H-indole,

[0062] 3-Guanidinocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole,

[0063] 3-Guanidinocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole,

[0064] 3-Guanidinocarbonyl-1-(2-methylquinol-4-yl)-1H-indole,

[0065] 3-Guanidinocarbonyl-1-(7-chloroquinol-4-yl)-1H-indole,

[0066] 3-Guanidinocarbonyl-1-(7-chloroquinol-4-yl)-5-methoxy-2-methyl-1H-indole,

[0067] 3-Guanidinocarbonyl-1-(6-fluoroquinol-4-yl)-1H-indole,

[0068] 3-Guanidinocarbonyl-1-(6-fluoroquinol-4-yl)-5-methoxy-2-methyl-1H-indole,

[0069] 3-Guanidinocarbonyl-1-(8-fluoroquinol-4-yl)-1H-indole,

[0070] and

[0071] 3-Guanidinocarbonyl-1-(6-chloro-quinazolin-4-yl)-5-methoxy-2-methyl-1H-indole, and tautomers thereof and pharmaceutically acceptable salts thereof.

[0072] If the inventive compounds contain one or more centers of asymmetry, these may independently of one another have the S and the R configuration. The compounds may be in the form of optical isomers, of diastereomers, of racemates or of mixtures thereof in any ratio.

[0073] The present invention encompasses all tautomeric forms of the compounds of the formula I.

[0074] Alkyl radicals may be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkylamino, alkylcarbonylamino, alkoxy, alkoxycarbonyl, alkylcarbonyl, polyfluoroalkyl or polyfluoroalkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl (=1-methylethyl), n-butyl, isobutyl (=2-methylpropyl), sec-butyl (=1-methylpropyl), tert-butyl (=1,1-dimethylethyl), pentyl or hexyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, tert-butyl and isobutyl. One or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms in alkyl radicals may be replaced by fluorine atoms to form polyfluoroalkyl radicals. Examples of such radicals are difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl; 3,3,3-trifluoropropyl, trifluorobutyl. Polyfluoroalkoxy radicals are alkoxy radicals of 1 to 3 carbons substituted by 1, 2, 3, 4, 5, 6 or 7 fluorine atoms, in particular trifluoromethoxy.

[0075] Examples of the group NRaRb in which Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated 5- or 6-membered heterocycle, are piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl or piperazin-1-yl.

[0076] 9- or 10-membered bicyclic heteroaryl radicals, having one, two or three nitrogen atoms, may be attached by all positions, for example by the 1 position, 2 position, 3 position, 4 position, 5 position, 6 position, 7 position or 8 position. Examples of these heteroaryl radicals are quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline, phthalazine or 7H-pyrrolo-[2,3-d]-pyrimidine. Substituted heteroaryl radicals may be substituted in any positions.

[0077] The halogen radicals are either chlorine, bromine, fluorine or iodine.

[0078] As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0079] “Patient” includes both human and other mammals.

[0080] “Effective amount” is meant to describe an amount of compound, composition, medicament or other active ingredient effective in producing the desired therapeutic effect.

[0081] The compounds of the formula I inhibit the cellular sodium-proton antiporter (Na⁺/H⁺-exchanger, NHE), in particular they inhibit the subtype NHE1. Because of the NHE-inhibitory properties, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by activation of or activated NHE, and of diseases caused secondarily by the NHE-related damage.

[0082] Patent EP 639 573 discloses heteroaroylguanidine derivatives as NHE inhibitors. Specific indole derivatives are disclosed, but no compounds with a substituted, bicyclic heteroaryl group in position 1 and with the guanidinocarbonyl in position 3.

[0083] Patent EP 622 356 discloses indoloylguanidines with a substituent on the nitrogen of the indole, which is hydrogen or a substituted or unsubstituted alkyl or a cycloalkyl or an OH or an alkoxy.

[0084] The compounds of the formula (I) can be used as novel medicaments in the treatment of diseases as inhibitors of NHE and in particular of NHE-1 with good selectivity for. NHE-1 with respect to NHE-2. This good selectivity makes it possible to reduce the potential gastrointestinal side effects existing with regard to molecules having inadequate selectivity (J. Clin. Invest., 1998, 101(6), 1243; Comparative Medicine, 2000, 50(5), 511).

[0085] Since NHE inhibitors predominantly act via their effect on cellular pH regulation, they can generally be combined beneficially with other compounds which regulate the intracellular pH, with suitable combination partners being, for example, inhibitors of the carbonate dehydratase enzyme group, inhibitors of systems transporting bicarbonate ions, such as of the sodium bicarbonate cotransporter (NBC) or of the sodium-dependent chloride-bicarbonate exchanger (NCBE), and NHE inhibitors with inhibitory effect on other NHE subtypes, because it is possible through them to enhance or modulate the pharmacologically relevant pH-regulating effects of the NHE inhibitors described herein.

[0086] The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine, in particular human medicine.

[0087] Thus, the NHE inhibitors of the invention are suitable for the treatment of diseases caused by ischemia and by reperfusion.

[0088] The compounds described herein are suitable because of their pharmacological properties as antiarrhythmic medicaments. Owing to their cardioprotective component, the NHE inhibitors of the formula I and/or the pharmaceutically acceptable salts thereof are outstandingly suitable for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris, in which cases they also preventively inhibit or greatly reduce the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof used according to the invention can, because of inhibition of the cellular Na⁺/H⁺ exchange mechanism, be used as medicaments for the treatment of all acute or chronic ischemia-induced damage or diseases induced primarily or secondarily thereby.

[0089] This also relates to their use as medicaments for surgical interventions. Thus, the compounds can be used during organ transplantations, it being possible to use the compounds both to protect the organs in the donor before and during the removal, to protect removed organs for example during treatment with or storage thereof in physiological bath liquids, and during transfer to the recipient organism.

[0090] The compounds of the invention are likewise valuable medicaments with a protective effect when performing angioplastic surgical interventions, for example on the heart as well as on peripheral organs and vessels. It has emerged that the compounds of the invention are exceptionally effective medicaments for life-threatening arrhythmias. Ventricular fibrillation is terminated and the physiological sinus rhythm of the heart is restored.

[0091] Since NHE1 inhibitors of human tissue and organs, especially the heart, protect effectively not only against damage caused by ischemia and reperfusion but also against the cytotoxic effect of medicaments like those used in particular in cancer therapy and the therapy of autoimmune diseases, combined administration with compounds of the formula I and/or the pharmaceutically acceptable salts thereof is suitable for inhibiting the cytotoxic, especially cardiotoxic, side effects of said compounds. The reduction in the cytotoxic effects, especially the cardiotoxicity, resulting from comedication with NHE1 inhibitors makes it additionally possible to increase the dose of the cytotoxic therapeutic agents and/or to prolong the medication with such medicaments. The therapeutic benefits of such a cytotoxic therapy can be considerably increased by combination with NHE inhibitors.

[0092] In addition, the NHE1 inhibitors of the invention of the formula I and/or the pharmaceutically acceptable salts thereof can be used when there is heart-damaging overproduction of thyroid hormones, thyrotoxicosis, or on external supply of thyroid hormones. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus suitable for improving therapy with cardiotoxic medicaments.

[0093] In accordance with their protective effect against ischemia-induced damage, the compounds of the invention are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the central nervous system, being suitable for example for the treatment of stroke or of cerebral edema.

[0094] The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are also suitable for the therapy and prophylaxis of diseases and disorders induced by overexcitability of the central nervous system, in particular for the treatment of epileptic disorders, centrally induced clonic and tonic spasms, states of psychological depression, anxiety disorders and psychoses. In these cases it is possible to use the NHE inhibitors described herein alone or in combination with other substances with antiepileptic activity or antipsychotic active ingredients, or carbonate dehydratase inhibitors, for example with acetazolamide, and with other inhibitors of NHE or of the sodium-dependent chloride-bicarbonate exchanger (NCBE).

[0095] The compounds according to the invention of the formula I and/or the pharmaceutically acceptable salts thereof are additionally likewise suitable for the treatment of types of shock such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

[0096] The compounds of the formula I and/or the pharmaceutically acceptable salts thereof can likewise be used for the prevention and treatment of thrombotic disorders because they, as NHE inhibitors, are able to inhibit platelet aggregation themselves. They are additionally able to inhibit or prevent the excessive release, occurring after ischemia and reperfusion, of mediators of inflammation and coagulation, especially of von Willebrand factor and of thrombogenic selectin proteins. It is thus possible to reduce and eliminate the pathogenic effect of significant thrombogenic factors. The NHE inhibitors of the present invention can therefore be combined with other anticoagulant and/or thrombolytic active ingredients such as, for example, recombinant or natural tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, medicinal substances with fibrinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor VIIa antagonists, clopidogrel, ticlopidine etc. Combined use of the present NHE inhibitors with NCBE inhibitors and/or with inhibitors of carbonate dehydratase such as, for example, with acetazolamide, is particularly beneficial.

[0097] The compounds of the formula I and/or the pharmaceutically acceptable salts thereof used according to the invention are additionally distinguished by a strong inhibitory effect on the proliferation of cells, for example fibroblast proliferation and the proliferation of smooth vascular muscle cells. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for diseases in which cellular proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents for chronic renal failure, cancers.

[0098] It was possible to show that cell migration is inhibited by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for diseases in which cell migration represents a primary or secondary cause, such as, for example, cancers with a pronounced tendency to metastasis.

[0099] The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are further distinguished by a retardation or prevention of fibrotic disorders. They are thus suitable as excellent agents for the treatment of cardiac fibroses, and of pulmonary fibrosis, hepatic fibrosis, renal fibrosis and other fibrotic disorders. They can thus be used for the treatment of organ hypertrophies and hyperplasias, for example of the heart and the prostate. They are therefore suitable for the prevention and treatment of heart failure (congestive heart failure=CHF) and for the treatment and prevention of prostate hyperplasia or prostate hypertrophy. Since there is significant elevation in NHE in essential hypertensives, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of high blood pressure and of cardiovascular disorders. In these cases they can be used alone or with a suitable combination and formulation partner for the treatment of high blood pressure and of cardiovascular disorders. Thus, for example, they can be combined with one or more diuretics with a thiazide-like action, loop diuretics, aldosterone and pseudoaldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone. The NHE inhibitors of the present invention can further be used in combination with calcium channel blockers such as verapamil, diltiazem, amlodipine or nifedipine, and with ACE inhibitors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Further beneficial combination partners are also beta-blockers such as metoprolol, albuterol etc., antagonists of the angiotensin receptor and its receptor subtypes such as losartan, irbesartan, valsartan; omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and activators of potassium channels such as glibenclamide, glimepiride, diazoxide, cromakalim, minoxidil and derivatives thereof, activators of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of Kv1.5 etc.

[0100] It has emerged that NHE1 inhibitors of the formula I and/or the pharmaceutically acceptable salts thereof have a significant antiinflammatory effect and can thus be used as antiinflammatory drugs. Inhibition of the release of mediators of inflammation is noteworthy in this connection. The compounds can thus be used alone or in combination with an antiinflammatory drug for the prevention or treatment of chronic and acute inflammatory disorders. Combination partners advantageously used are steroidal and non-steroidal antiinflammatory drugs. The compounds of the invention can also be used for the treatment of disorders caused by protozoa, of malaria and of coccidiosis in poultry.

[0101] It has additionally been found that compounds of the formula I and/or the pharmaceutically acceptable salts thereof show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood fat levels which are too high, called hyperlipoproteinemias, represent an essential risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. Besides the reduction in total serum cholesterol, it is particularly important to reduce the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular of the low density lipoproteins (LDL) and of the very low density lipoproteins (VLDL), because these lipid fractions represent an atherogenic risk factor. By contrast, a protective function against coronary heart disease is ascribed to the high density lipoproteins. Accordingly, hypolipidemics should be able to reduce not only total cholesterol but, in particular, the VLDL and LDL serum cholesterol fractions. It has now been found that NHE1 inhibitors show valuable therapeutically utilizable properties in relation to influencing the serum lipid levels. Thus, they significantly reduce the elevated serum concentrations of LDL and VLDL as are to be observed, for example, due to increased dietary intake of a cholesterol- and lipid-rich diet or in cases of pathological metabolic alterations, for example genetically related hyperlipidemias. They can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor. Included herein are not only the primary hyperlipidemias but also certain secondary hyperlipidemias occurring, for example, in association with diabetes. In addition, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof lead to a marked reduction in the infarctions induced by metabolic abnormalities and, in particular, to a significant reduction in the induced infarct size and the severity thereof. Said compounds are therefore advantageously used for producing a medicament for the treatment of hypercholesterolemia; for producing a medicament for the prevention of atherogenesis; for producing a medicament for the prevention and treatment of atherosclerosis, for producing a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels, for producing a medicament for the prevention and treatment of diseases induced by endothelial dysfunction, for producing a medicament for the prevention and treatment of atherosclerosis-induced hypertension, for producing a medicament for the prevention and treatment of atherosclerosis-induced thromboses, for producing a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced ischemic damage and post-ischemic reperfusion damage, for producing a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced cardiac hypertrophies and cardiomyopathies and of congestive heart failure (CHF), for producing a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced coronary vasospasms and myocardial infarctions, for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula I and/or the pharmaceutically acceptable salts thereof with an active ingredient lowering the blood fat levels, preferably with an HMG-COA reductase inhibitor (for example lovastatin or pravastatin), the latter bringing about a hypolipidemic effect and thus increasing the hypolipidemic properties of the NHE inhibitor of the formula I and/or the pharmaceutically acceptable salts thereof, proves to be a favorable combination with enhanced effect and reduced use of active ingredients.

[0102] Thus, compounds of the formula I and/or the pharmaceutically acceptable salts thereof lead to effective protection against endothelial damage of various origins. This protection of the vessels against the syndrome of endothelial dysfunction means that the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are valuable medicaments for the prevention and treatment of coronary vasospasms, peripheral vascular diseases, in particular intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders.

[0103] It has additionally been found that compounds of the formula I and/or the pharmaceutically acceptable salts thereof are suitable in the treatment of non-insulin-dependent diabetes (NIDDM), with the insulin resistance being restrained. It may in this connection be beneficial, to enhance the antidiabetic activity and quality of the effect of the compounds of the invention, to combine them with a biguanide such as metformin, with an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide etc., with a glucosidase inhibitor, with a PPAR agonist such as rosiglitazone, pioglitazone etc., with an insulin product of different administration form, with a DB4 inhibitor, with an insulin sensitizer or with meglitinide.

[0104] Besides the acute antidiabetic effects, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof counteract the development of late complications of diabetes and can therefore be used as medicaments for the prevention and treatment of late damage from diabetes, such as diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy and other disorders occurring as a consequence of diabetes. They can in this connection be advantageously combined with the antidiabetic medicaments just described under NIDDM treatment. The combination with a beneficial dosage form of insulin should be particularly important in this connection.

[0105] The NHE inhibitors of the invention of the formula I and/or the pharmaceutically acceptable salts thereof show, besides the protective effects against acute ischemic events and the subsequent equally acutely stressing reperfusion events, also direct therapeutically utilizable effects against diseases and disorders of the entire mammalian organism which are associated with the manifestations of the chronically progressive aging process and which occur independently of acute hypoperfusion states and under normal, non-ischemic conditions. These pathological, age-related manifestations induced over the long aging period, such as illness, invalidity and death, which can now be made amenable to treatment with NHE inhibitors, are diseases and disorders which are essentially caused by age-related changes in vital organs and the function thereof and become increasingly important in the aging organism.

[0106] Disorders connected with an age-related functional impairment or with age-related manifestations of wear of organs are, for example, the inadequate response and reactivity of the blood vessels to contraction and relaxation reactions. This age-related decline in the reactivity of vessels to constricting and relaxing stimuli, which are an essential process of the cardiovascular system and thus of life and health, can be significantly eliminated or reduced by NHE inhibitors. One important function and a measure of the maintenance of the reactivity of vessels is the blockade or retardation of the age-related progression in endothelial dysfunction, which can be eliminated highly significantly by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the treatment and prevention of the age-related progression in endothelial dysfunction, especially of intermittent claudication.

[0107] An example of another variable characterizing the aging process is the decline in the contractability of the heart and the decline in the adaptation of the heart to a required pumping output of the heart. This diminished efficiency of the heart as a consequence of the aging process is in most cases connected with a dysfunction of the heart which is caused inter alia by deposition of connective tissue in the myocardial tissue. This deposition of connective tissue is characterized by an increase in the weight of the heart, by an enlargement of the heart and by restrictive cardiac function. It was surprising that it was possible almost completely to inhibit such aging of the heart organ. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the treatment and prevention of heart failure, of congestive heart failure (CHF).

[0108] Whereas preceding patents and patent applications have claimed the treatment of various forms of cancer which have already occurred, it was now extremely surprising that not only is it possible to cure a cancer which has already occurred through inhibition of proliferation, but there is also prevention and highly significant retardation of the age-related incidence of cancer through NHE inhibitors. A particularly noteworthy finding is that the disorders, occurring as a result of aging, of all organs and not only certain types of cancer are suppressed or occur with a highly significant delay. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the treatment and, in particular, the prevention of age-related types of cancer.

[0109] There is now found to be not only a delay, shifted highly significantly in time and beyond the normal statistical extent, in the occurrence of age-related disorders of all the organs investigated, including the heart, vessels, liver etc., and a highly significant delay in cancer of the elderly. On the contrary, there is also surprisingly a prolongation of life to an extent which has to date been achievable by no other group of medicaments or by any natural products. This unique effect of NHE inhibitors also makes it possible, besides the use of the active ingredients alone on humans and animals, to combine these NHE inhibitors with other active principles, measures, substances and natural products which are used in gerontology and which are based on a different mechanism of action. Such classes of active ingredients used in gerontological therapy are: in particular vitamins and substances with antioxidant activity. Since there is a correlation between caloric load or food intake and the aging process, the combination with dietary measures can take place for example with appetite suppressants. It is likewise possible to consider a combination with hypotensive medicaments such as with ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca²⁺ antagonists etc. or with metabolism-normalizing medicaments such as cholesterol-lowering agents.

[0110] The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the prevention of age-related tissue changes and for prolonging life while retaining a high quality of life.

[0111] The compounds of the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger) which in a large number of disorders (essential hypertension, atherosclerosis, diabetes etc.) is also increased in cells which are readily amenable to measurements, such as, for example, in erythrocytes, platelets or leucocytes. The compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostic agents for determining and distinguishing different types of hypertension, but also of atherosclerosis, diabetes and the late complications of diabetes, proliferative disorders etc.

[0112] The present invention also relates to processes for synthesising 3-guanidinocarbonyl-1-heteroaryl-indole derivatives of the formula (I).

[0113] The compounds of the general formula (I) can be prepared from the 3-alkoxycarbonyl-1H-indoles of the formula (II) in accordance with the following general synthetic scheme:

[0114] The general synthetic scheme is as follows:

[0115] a) a heteroaryl halide ArX of the formula (VI) is reacted with 3-alkoxycarbonyl-1H-indole of the formula (II)

[0116] b) the obtained 3-alkoxycarbonyl-1-heteroaryl-indole of the formula (III) is saponified

[0117] c) the 3-carboxy-1-heteroaryl-indole of the formula (IV) is converted in the acid chloride of formula (V)

[0118] d) the obtained product of formula (V) is reacted with guanidine

[0119] wherein in the compounds of the formula II, III, IV, V and VI

[0120] Ar and R1 to R3 are defined as in the compounds of the formula I,

[0121] X is F, Cl, Br or I and

[0122] R is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0123] The product is isolated and is optionally converted into a pharmaceutically acceptable salt.

[0124] The compounds of the general formulae (II) and (VI) that are not commercially available can be obtained by application or adaptation of the methods described in the literature, for example by Toyota M. et al., J. Chem. Soc. Perkin Trans. 1 (1992), (5), 547-52 and in WO 00/71537, each of which is incorporated herein by reference.

[0125] Reaction (a) between a suitable 3-alkoxycarbonyl-1H-indole of the formula (II) and a suitable heteroaryl halide ArX of the formula (VI) is preferably performed under an inert atmosphere (for example under nitrogen or under argon) in a basic medium, for example in the presence of potassium carbonate in an inert solvent, such as dimethyl sulphoxide, at a temperature of between 20° C. and the boiling point of the reaction medium, preferably at a temperature in the region of 100° C., or in the presence of sodium hydride in an inert solvent, such as dimethylformamide, at a temperature of between 20° C. and the boiling point of the reaction medium, preferably at a temperature in the region of 120° C.

[0126] Alternatively, the reaction (a) between a suitable 3-alkoxycarbonyl-1H-indole of the formula (II) and a suitable heteroaryl halide ArX of the formula (VI) can be performed preferably under an inert atmosphere (for example under nitrogen or under argon) in a basic medium, for example in the presence of potassium orthophosphate, copper iodide and trans-1,2-cyclohexanediamine, in an inert solvent, such as a mixture of 1,4-dioxane and n-dodecane, at a temperature of between 20° C. and the boiling point of the reaction medium, preferably at a temperature in the region of 100° C. Reaction (b) is generally performed according to the usual methods that do not affect the rest of the molecule, in particular by applying the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd ed.), A. Wiley, Interscience Publication (1991), or by McOmie, Protective Groups in Organic Chemistry, Plenum Press (1973), or by Bradford P. Mundy and Michael G. Ellerd, Name Reactions and Reagents in Organic Synthesis, A. Wiley, Interscience Publication (1988) each of which is incorporated herein by reference. For example, the saponification reaction (b) of a suitable 3-alkoxycarbonyl-1-heteroaryl-1H-indole of the formula (III) is performed in a basic medium, for example in the presence of lithium hydroxide monohydrate, in an inert solvent, such as a mixture of tetrahydrofuran and water, at a temperature of between 20° C. and the boiling point of the reaction medium, preferably at the reflux point of the reaction medium.

[0127] Reaction (c) is generally performed according to the usual methods that do not affect the rest of the molecule, in particular by applying the methods described by Bradford P. Mundy and Michael G. Ellerd, Name Reactions and Reagents in Organic Synthesis, A. Wiley, lnterscience Publication (1988), incorporated herein by reference. For example, the reaction (c) for the formation of the acid chloride of a suitable 3-carboxy-1-heteroaryl-1H-indole of the formula (IV) is preferably performed under an inert atmosphere (for example under nitrogen or under argon) in the presence of oxalyl chloride in an inert solvent, such as dichloromethane, at a temperature of between 20° C. and the boiling point of the reaction medium, preferably at a temperature in the region of 20° C., or in the presence of sulphinyl chloride in an inert solvent, such as chloroform, at a temperature of between 20° C. and the boiling point of the reaction medium, preferably at the reflux point of the reaction medium.

[0128] Reaction (d) between a suitable 3-chlorocarbonyl-1-heteroaryl-1H-indole of the formula (V) and guanidine is preferably performed under an inert atmosphere (for example under nitrogen or under argon) in an inert solvent, such as 1,2-dimethoxyethane or tetrahydrofuran, at a temperature in the region of 200.

[0129] The compounds of the formula (I) are isolated and can be purified by the usual known methods, for example by crystallisation, chromatography or extraction.

[0130] The compounds of the formula I can optionally be converted into addition salts with an inorganic or organic acid by reacting with such an acid in a solvent, e.g. an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention. Examples of pharmaceutically acceptable salts that can be mentioned include the following salts: benzenesulphonate, hydrobromide, hydrochloride, acetate, citrate, ethanesulphonate, fumarate, gluconate, iodate, maleate, isethionate, methanesulphonate, methylenebis(β-oxynaphthoate), nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulphate, tartrate, theophyllinacetate and p-toluenesulphonate.

[0131] If the compounds contain an acid group, they are capable of forming salts with bases, for example alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for example salts with ammonia or organic amines or amino acids. They can also be present as zwitterions.

[0132] The examples that follow illustrate the invention.

EXAMPLE 1 a) 3-Guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride

[0133]

[0134] 20 cm³ of methanol and 8.4 cm³ (4.2 mmol) of a 0.5N solution of sodium methoxide in methanol are added to 0.401 g (4.2 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm³ of dichloromethane and concentrated to dryness under reduced pressure (2.7 kPa). 40 cm³ of tetrahydrofuran and 0.35 g (0.85 mmol) of 3-chlorocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm³ of dichloromethane, are then added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the solid obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.1 g of 3-guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 216° C. Mass spectrum (EI): m/e 397 (M^(+.)), m/e 339 (base peak).

b) 3-Chlorocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride

[0135] 5 cm³ of thionyl chloride are added to 0.3 g (0.84 mmol) of 3-carboxy-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.35 g of 3-chlorocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.

c) 3-Carboxy-1-(2-(trifluoromethyl)quinol-4-yl )-1H-indole

[0136] 0.204 g (4.9 mmol) of lithium hydroxide monohydrate and 8 cm³ of water are added to 0.6 g (1.62 mmol) of 3-methoxycarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm³ of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm³ of water (pH=10). The resulting aqueous solution is washed with 30 cm³ of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm³ of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm³ of isbpropyl ether and filtered off, resulting in 0.3 g of 3-carboxy-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 356 (M^(+.)), m/e 311.

d) 3-Methoxycarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole

[0137] 1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-2-(trifluoromethyl)quinoline are added to 0.526 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm³ of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm³ of ethyl acetate and 100 cm³ of water. The organic phase is separated off by settling and washed with twice 100 cm³ of water and 100 cm³ of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm³ of isopropyl ether and the resulting precipitate is filtered off, giving 0.6 g of 3-methoxycarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M^(+.)), m/e 339.

EXAMPLE 2 a) 3-Guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride

[0138]

[0139] 20 cm³ of methanol and 20 cm³ (10 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.955 g (10 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm³ of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 40 cm³ of tetrahydrofuran and 0.75 g (2 mmol) of 3-chlorocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm³ of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the solid obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.54 g of 3-guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 260° C. Mass spectrum (EI): m/e 397 (M^(+.)), m/e 339 (base peak).

b) 3-Chlorocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride

[0140] 5 cm³ of thionyl chloride are added to 0.713 g (2 mmol) of 3-carboxy-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 20 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.85 g of 3-chlorocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.

c) 3-Carboxy-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole

[0141] 0.32 g (7.63 mmol) of lithium hydroxide monohydrate and 8 cm³ of water are added to 0.94 g (2.54 mmol) of 3-methoxycarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm³ of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm³ of water (pH=10). The resulting aqueous solution is washed with 30 cm³ of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm³ of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.73 g of 3-carboxy-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum: m/e 356 (M^(+.)).

d) 3-Methoxycarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole

[0142] 1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-6-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm³ of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm³ of ethyl acetate and 100 cm³ of water. The organic phase is separated off by settling and washed with twice 100 cm³ of water and 100 cm³ of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm³ of isopropyl ether and the resulting precipitate is filtered off, giving 0.94 g of 3-methoxycarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M^(+.)), m/e 339.

EXAMPLE 3 a) 3-Guanidinocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride

[0143]

[0144] 20 cm³ of methanol and 14 cm³ (7 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.67 g (7 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm³ of dichloromethane and concentrated to dryness under reduced pressure (2.7 kPa). 40 cm³ of tetrahydrofuran, 40 cm³ of dichloromethane and 0.525 g (1.4 mmol) of 3-chlorocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm³ of tetrahydrofuran, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.1 g of 3-guanidinocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 238° C. Mass spectrum (EI): m/e 397 (M^(+.)), m/e 339 (base peak).

b) 3-Chlorocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl )-1H-indole hydrochloride

[0145] 5 cm³ of thionyl chloride are added to 0.5 g (1.4 mmol) of 3-carboxy-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.58 g of 3-chlorocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.

c) 3-Carboxy-1-(7-(trifluoromethyl)quinol-4-yl )-1H-indole

[0146] 0.33 g (7.77 mmol) of lithium hydroxide monohydrate and 8 cm³ of water are added to 0.96 g (2.59 mmol) of 3-methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm³ of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm³ of water (pH=10). The resulting aqueous solution is washed with 30 cm³ of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm³ of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.59 g of 3-carboxy-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 356 (M^(+.)), m/e 311.

d) 3-Methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole

[0147] 1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-7-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm³ of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm³ of ethyl acetate and 100 cm³ of water. The organic phase is separated off by settling and washed with twice 100 cm³ of water and 100 cm³ of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm³ of isopropyl ether and the resulting precipitate is filtered off, giving 0.96 g of 3-methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M^(+.)), m/e 339.

EXAMPLE 4 a) 3-Guanidinocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride

[0148]

[0149] 20 cm³ of methanol and 14 cm³ (7 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.67 g (7 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm³ of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 30 cm³ of tetrahydrofuran and 0.525 g (1.4 mmol) of 3-chlorocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 30 cm³ of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm³ of diisopropyl ether and filtered off, resulting in 0.14 g of 3-guanidinocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 212° C. Mass spectrum (EI): m/e 397 (M^(+.)), m/e 339 (base peak).

b) 3-Chlorocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole

[0150] 5 cm³ of thionyl chloride are added to 0.5 g (1.4 mmol) of 3-carboxy-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.58 g of 3-chlorocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.

c) 3-Carboxy-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole

[0151] 0.32 g (7.62 mmol) of lithium hydroxide monohydrate and 8 cm³ of water are added to 0.94 g (2.54 mmol) of 3-methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm³ of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm³ of water (pH=10). The resulting aqueous solution is washed with 30 cm³ of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm³ of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.50 g of 3-carboxy-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 356 (M^(+.)).

d) 3-Methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole

[0152] 1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-8-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm³ of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm³ of ethyl acetate and 100 cm³ of water. The organic phase is separated off by settling and washed with twice 100 cm³ of water and 100 cm³ of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm³ of isopropyl ether and the resulting precipitate is filtered off, giving 0.94 g of 3-methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M^(+.)), m/e 339.

EXAMPLE 5 a) 3-Guanidinocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride

[0153]

[0154] 20 cm³ of methanol and 17 cm³ (8.5 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.812 g (8.5 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm³ of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 40 cm³ of tetrahydrofuran and 0.67 g (1.79 mmol) of 3-chlorocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride, suspended in 40 cm³ of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.37 g of 3-guanidinocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 266° C. Mass spectrum (EI): m/e 359 (M^(+.)), m/e 301.

b) 3-Chlorocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride

[0155] 4 cm³ of thionyl chloride are added to 0.57 g (1.79 mmol) of 3-carboxy-1-(6-methoxyquinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.67 g of 3-chlorocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.

c) 3-Carboxy-1-(6-methoxyquinol-4-yl)-1H-indole

[0156] 0.252 g (6 mmol) of lithium hydroxide monohydrate and 8 cm³ of water are added to 0.7 g (2.11 mmol) of 3-methoxycarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole dissolved in 8 cm³ of tetrahydrofuran. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm³ of water (pH=10). The resulting aqueous solution is washed with 30 cm³ of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with a mixture of 50 cm³ of ethyl acetate and of 100 cm³ of dichloroethane. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.57 g of 3-carboxy-1-(6-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 318 (M^(+.)).

d) 3-Methoxycarbonyl-1-(6-methoxyquinol-4-yl )-1H-indole

[0157] 1.73 g (12.5 mmol) of potassium carbonate and 0.968 g (5 mmol) of 4-chloro-6-methoxyquinoline are added to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 20 cm³ of dimethylacetamide under an argon atmosphere. After stirring at a temperature in the region of 140° C. for 20 hours, the reaction mixture is cooled and diluted with 200 cm³ of ethyl acetate and 200 cm³ of water. The organic phase is separated off by settling and washed with three times 200 cm³ of water and 200 cm³ of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. Concentrating these fractions to dryness under reduced pressure (2.7 kPa) results in 0.7 g of 3-methoxycarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 332 (M^(+.)), m/e 301.

EXAMPLE 6 a) 3-Guanidinocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole hydrochloride

[0158]

[0159] 20 cm³ of methanol and 30 cm³ (15 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 1.43 g (15 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm³ of dichloromethane and concentrated to dryness under reduced pressure (2.7 kPa). 40 cm³ of tetrahydrofuran and 1.05 g (2.8 mmol) of 3-chlorocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole hydrochloride, suspended in 40 cm³ of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm³ of isopropyl ether and filtered off, resulting in 0.82 g of a white solid. The recrystallisation of this solid from 40 cm³ of ethanol under hot conditions gives 0.48 g of 3-guanidinocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 266° C. Mass spectrum (EI): m/e 359 (M^(+.)), m/e 301.

b) 3-Chlorocarbonyl-1-(7-methoxyquinol-4-yl )-1H-indole hydrochloride

[0160] 6 cm³ of thionyl chloride are added to 0.9 g (2.83 mmol) of 3-carboxy-1-(7-methoxyquinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.05 g of 3-chlorocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.

c) 3-Carboxy-1-(7-methoxyquinol-4-yl)-1H-indole

[0161] 0.504 g (12 mmol) of lithium hydroxide monohydrate and 20 cm³ of water are added to 1.3 g (3.91 mmol) of 3-methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole dissolved in 20 cm³ of tetrahydrofuran. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm³ of water (pH=10). The resulting aqueous solution is washed with 50 cm³ of ethyl acetate and adjusted to pH 6 with N hydrochloric acid. The resulting precipitate is filtered off and then it is rinsed with three times 20 cm³ of water and twice 20 cm³ of isopropyl ether and dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. to give 0.9 g of 3-carboxy-1-(7-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 318 (M^(+.)).

d) 3-Methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole

[0162] 3.46 g (25 mmol) of potassium carbonate and 1.94 g (10 mmol) of 4-chloro-7-methoxyquinoline are added to 1.75 g (10 mmol) of 3-methoxycarbonyl-1H-indole in 50 cm³ of dimethylacetamide under an argon atmosphere. After stirring at a temperature in the region of 140° C. for 20 hours, the reaction mixture is cooled and diluted with 300 cm³ of ethyl acetate and 300 cm³ of water. The organic phase is separated off by settling and washed with three times 300 cm³ of water and 300 cm³ of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), 1.7 g of 3-methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole are obtained in the form of a yellow foam. Mass spectrum (EI): m/e 332 (M^(+.)), m/e 301.

e) 4-Chloro-7-methoxyquinoline Can be Obtained by the Method Described by M. Lauer et al., J. Amer. Chem. Soc. (1946), 48, 1268. EXAMPLE 7 a) 3-Guanidinocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole hydrochloride

[0163]

[0164] 0.345 g (15 mmol) of sodium (prewashed in toluene) is added gradually to 100 cm³ of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolution with stirring, 1.43 g (15 mmol) of guanidine hydrochloride are added, and the reaction mixture is stirred at a temperature in the region of 20° C. for 2 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa), and the residue is taken up twice successively with 70 cm³ of dichloromethane (stabilized with amylene) and concentrated to dryness under reduced pressure (2.7 kPa). 50 cm³ of tetrahydrofuran and 50 cm³ of dichloromethane are then added, under an argon atmosphere, at a temperature in the region of 20° C., and 3 mmol of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole hydrochloride, are then added with stirring. After stirring for 15 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluent: ethyl acetate/methanol (80/20 by volume)]. After the various fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), the solid obtained is taken up in methanol, and the mixture is refluxed for 10 minutes. After cooling to a temperature in the region of 20° C. and filtered, the solid is dried at a temperature in the region of 40° C. under reduced pressure (2.7 kPa), giving 0.45 g of 3-guanidinocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-1H-indole hydrochloride in the form of an off-white solid melting at 244° C. Mass spectrum (DCI): m/e 334 (MH⁺) (base peak).

b) 3-Chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimid in-4-yl )-1H-indole hydrochloride

[0165] 6 cm³ of thionyl chloride are added to 0.9 g (3.08 mmol) of 3-carboxy-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole at a temperature in the region of 20° C. under an argon atmosphere. After stirring under reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), triturated twice successively with 30 cm³ of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa), giving 0.92 g of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole hydrochloride in the form of a yellow powder, which is used directly in the following step.

c) 3-Carboxy-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-1H-indole

[0166] 0.629 g (15 mmol) of lithium hydroxide monohydrate and 20 cm³ of water are added to 1.35 g (4.41 mmol) of 3-methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole dissolved in 20 cm³ of tetrahydrofuran at a temperature in the region of 20° C. After stirring for 4 hours at the reflux temperature of the solvent and for 24 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm³ of water (pH=12) and extracted with 100 cm³ of ethyl acetate. The pH is then adjusted to 6 by adding 1 N hydrochloric acid solution. The precipitate obtained is filtered off and dried at a temperature in the region of 50° C. under reduced pressure (2.7 kPa), giving 1.0 g of 3-carboxy-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 292 (M+) (base peak).

d) 3-Methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-1H-indole

[0167] 1.40 g (8 mmol) of 3-methoxycarbonyl-1H-indole are added to 30 cm³ of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere, and 0.32 g (10 mmol) of sodium hydride are then added. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, 1.35 g (8.05 mmol) of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 10 cm³ of dimethylformamide are then added, and the mixture is heated at a temperature in the region of 100° C. for 16 hours. The reaction mixture is then cooled to a temperature in the region of 20° C. and then poured into a mixture of 200 cm³ of ethyl acetate and 200 cm³ of water. The organic phase is separated out after the phases have settled, washed with twice 200 cm³ of water and then with 200 cm³ of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (80/20 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), 1.35 g of 3-methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole are obtained in the form of an off-white solid. Mass spectrum (EI): m/e 306 (M⁺) (base peak).

e) 4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine

[0168] 0.4 g (12.5 mmol) of sodium hydride is added to 25 cm³ of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C., and a solution of 1.8 g (11.7 mmol) of 4-chloropyrrolo[2,3-d]pyrimidine in 25 cm³ of dimethylformamide is then added dropwise over the course of 15 minutes. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, 1.12 cm³ (18 mmol) of methyl iodide are then added, and stirring is continued for 15 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of 200 cm³ of ethyl acetate and 200 cm³ of water. The organic phase is separated out after the phases have settled, washed successively twice with 200 cm³ of water and 200 cm³ of saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa), giving 1.35 g of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in the form of a brown powder. Mass spectrum (DCI): m/e 168 (MH⁺) (base peak).

EXAMPLE 8 a) N-[1-(2-Methyl-quinolin-4-yl)-1H-indole-3-carbonyl]-guanidine trifluoroacetate

[0169]

[0170] A solution of guanidine in dry DMF is prepared by stirring 5 mmol (560 mg) of potassium t-butoxide and 5.5 mmol (525 mg) of guanidine hydrochloride in 5 ml DMF for 30 minutes at room temperature under exclusion of moisture. To the resulting suspension is added the methyl ester obtained above, the mixture is stirred for 18 h at room temperature under argon. The mixture is filtered and the filtrate directly subjected to purification by prep HPLC (acetonitrile/H₂O+0.1% trifluoroactetic acid) to yield N-[1-(2-methyl-quinolin-4-yl)-1H-indole-3-carbonyl]-guanidine trifluoroacetate as a foam. The product was characterized by analytical HPLC/MS (Waters 1525 HPLC with Micromass MUX-LCT MS detector; column Merck-Purospher 55*2 mm, 3μ RP18; column temperature: room temperature; gradient (H₂O+0.1% formic acid):(acetonitrile+0.1% formic acid) from 95:5 (0 min) to 5:95 (5 min) to 5:95 (7 min)).

[0171] Retention time: 2.13 min, MS molpeak 343 (M+H, electrospray ionisation)

b) 1-(2-Methyl-quinolin-4-yl)-1H-indole-3-carboxylic acid methyl ester

[0172] 1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) of 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs₂CO₃ are suspended in 3 ml of dry DMF. The mixture is stirred for 60h at 80 ° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na₂SO₄ and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(2-methyl-quinolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 316.12 (M+H, electrospray ionisation)) as an off-white foam after freeze-drying. following compounds are prepared in analogy to example 8: 9

N-[1-(7-Chloro-quinolin-4-yl)-1H-indole- 3-carbonyl]-guanidine trifluoroacetate Retention time: 2.54 min, MS: 364 (M + H) 10

N-[1-(7-Chloro-quinolin-4-yl)-5-methoxy- 2-methyl-1H-indole-3-carbonyl]- guanidine trifluoroacetate Retention time: 3.14 min, MS: 408 (M + H) 11

N-[1-(6-Fluoro-quinolin-4-yl)-1H-indole- 3-carbonyl]-guanidine trifluoroacetate Retention time: 2.40 min, MS: 348 (M + H) 12

N-[1-(6-Fluoro-quinolin-4-yl)-5-methoxy- 2-methyl-1H-indole-3-carbonyl]- guanidine trifluoroacetate Retention time: 2.36 min MS: 392 (M + H) 13

N-[1-(8-Fluoro-quinolin-4-yl)-1H-indole- 3-carbonyl]-guanidine trifluoroacetate Retention time: 2.39 min, MS: 348 (M + H) 14

N-[1-(6-Chloro-quinazolin-4-yl)-5- methoxy-2-methyl-1H-indole-3- carbonyl]-guanidine trifluoroacetate Retention time: 2.38 min, MS: 409 (M + H)

[0173] NHE Inhibition Methods

[0174] The NHE inhibitory activities (IC₅₀ values) of the compounds according to the invention were determined by a FLIPR test.

[0175] The test is performed in the FLIPR (Fluorescent Imaging Plate Reader) equipped with clear-bottomed and black-walled 96-well microtitration plates. The transfected cell lines expressing the various NHE subtypes (the parental cell line LAP-1 shows no endogenous NHE activity as a result of mutagenesis and subsequent selection) are seeded the preceding day at a density of ˜25 000 cells/well.

[0176] The growth medium for the transfected cells (Iscove+10% foetal calf serum) also comprises G418 as selection antibiotic to ensure the presence of transfected sequences.

[0177] The actual test begins by eliminating the growth medium and adding 100 μl of loading buffer per well (5 μM of BCECF-AM [2′,7′-bis(2-carboxyethyl)-5-(6)-carboxyfluoresceine acetoxymethyl ester] in 20 mM of NH₄Cl, 115 mM of choline chloride, 1 mM of CaCl₂, 5 mM of KCl, 20 mM of HEPES and 5 mM of glucose; pH 7.4 (adjusted with KOH). The cells are then incubated for 20 minutes at 37° C. This incubation results in the loading of the fluorescent dye into the cells, the fluorescence intensity of which depends on the pH_(i), and on the NH₄Cl, which results in a slight basification of the cells.

[0178] The precursor BCECF-AM, a non-fluorescent dye, is, as an ester, capable of crossing the membrane. The actual dye, which is incapable of crossing the membrane, is released inside the cell by esterases.

[0179] After this 20-minute incubation, the loading buffer, which comprises NH₄Cl and free BCECF-AM, is removed by washing three times in the cell washing device (Tecan Columbus), each wash being performed with 400 μl of washing buffer (133.8 mM of choline chloride, 4.7 mM of KCl, 1.25 mM of MgCl₂, 1.25 mM of CaCl₂, 0.97 mM of K₂HPO₄, 0.23 mM of KH₂PO₄, 5 mM of HEPES and 5 mM of glucose; pH 7.4 (adjusted with KOH)). The residual volume remaining in the wells is 90 μl (possibly between 50 and 125 μl). This washing step removes the free BCECF-AM and results in an intracellular acidification (pH_(i) of 6.3-6.4) due to the removal of the external ammonium ions.

[0180] As the equilibrium of the intracellular ammonium with the aqueous ammonia and the protons, by removal of the extracellular ammonium and by the subsequent immediate crossing of the aqueous ammonia across the cell membrane, is disrupted, the washing process results in intracellular protons remaining, which is the cause of the intracellular acidification. This acidification can result finally in the death of the cells if it lasts long enough. It is important here for the washing buffer to be free of sodium (<1 mM), otherwise the extracellular sodium ions would result in an immediate increase in the pH_(i) on account of the activity of the cloned NHE isoforms. It is also important for all the buffers used (loading buffer, washing buffer and regeneration buffer) not to contain any HCO₃-ions, otherwise the presence of bicarbonate would result in the activation of bicarbonate-dependent systems that disrupt the pH_(i) regulation, which systems are contained in the LAP-1 parental cell line.

[0181] The microtiter plates containing acidified cells are then transferred (up to 20 minutes after the acidification) to the FLIPR. In the FLIPR, the intracellular fluorescent dye is activated with light of a wavelength of 488 nm, which is generated by an argon laser, and the measuring parameters (laser power, illumination time and diaphragm of the CDD camera integrated into the FLIPR) are chosen such that the average value of the fluorescent signal per well is between 30,000 and 35,000 relative fluorescence units.

[0182] The actual measurement in the FLIPR starts with a photograph being taken by the CCD camera every two seconds under software control. After 10 seconds, the increase in the intracellular pH is initiated by adding 90 μl of regeneration buffer (133.8 mM of NaCl, 4.7 mM of KCl, 1.25 mM of MgCl₂, 1.25 mM of CaCl₂, 0.97 mM of K₂HPO₄, 0.23 mM of KH₂PO₄, 10 mM of HEPES and 5 mM of glucose; pH 7.4 (adjusted with NaOH)) using a 96-well pipette device incorporated into the FLIPR. Some wells, to which is added pure regeneration buffer, serve as positive controls (100% NHE activity). The negative controls (0% NHE activity) contain washing buffer. Regeneration buffer with twice the concentration of test substance is added to all the other wells. Measurement in the FLIPR terminates after 60 measurements (two minutes).

[0183] The experimental data allow the NHE activities to be calculated for each concentration of test substance and, from these, the IC₅₀ values of the substances. For the NHE-1 subtype the following results are obtained. example No. IC50 (NHE1)/μM 1 2.36 2 0.22 3 0.25 4 1.47 5 0.12 6 0.24 7 0.0012 8 0.0072 9 0.25 10 3.23 11 0.010 12 2.64 13 0.0025 14 2.56

[0184] The invention relates also to the use of the compounds of the formula I and/or pharmaceutically acceptable salts thereof for the preparation of medicaments and pharmaceutical compositions as inhibitors of the NHE. Claimed is a medicine for human, veterinary or phytoprotective use, comprising an effective amount of a compound of the formula I and/or the pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers and additives, alone or in combination with other active pharmaceutical ingredients or medicaments.

[0185] The pharmaceutical compositions according to the invention consist of a compound of the formula I and/or the pharmaceutically acceptable salt thereof, in pure form or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be administered, for example, orally, parenterally, intravenously, rectally, transdermally, topically or by inhalation. The medicaments generally comprise active ingredients of the formula I and/or pharmaceutically acceptable salts therof in an amount of from 0.001 mg to 1 g per dose unit.

[0186] The excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients, and other active ingredient carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavourings, preservatives, solubilizers or colors.

[0187] For a pharmaceutical formulation for oral administration, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. It is moreover possible for the preparation to take place both as dry granules and as wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.

[0188] Tablets, pills, powders (gelatine capsules or cachets) or granules can be used as solid compositions for oral administration. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions may also comprise substances other than diluents, for example one or more lubricants, such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish. Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs comprising inert diluents, such as water, ethanol, glycerol, plant oils or liquid paraffin, can be used as liquid compositions for oral administration. These compositions may comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavourings or stabilisers.

[0189] The sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Solvents or vehicles that can be used include water, propylene glycol, a polyethylene glycol, plant oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents. These compositions may also comprise adjuvants, in particular wetting agents, tonicity agents, emulsifiers, dispersants and stabilisers. The sterilisation may be performed in several ways, for example by aseptic filtration, by incorporating sterilising agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions that may be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0190] The compositions for rectal administration are suppositories or rectal capsules that comprise, besides the active product, excipients, such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

[0191] The compositions for topical administration may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

[0192] For subcutaneous, intramuscular or intravenous administration, the active compounds used are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients, into a solution, suspension or emulsion. Examples of suitable solvents are: water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.

[0193] Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I and/or the pharmaceutically acceptable salts thereof in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents. The formulation may, if required, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a preparation contains, for example, the active ingredient in a concentration of about 0.1 to 10, in particular of about 0.3 to 3% by weight.

[0194] The dosage of the active ingredient of the formula I to be administered, and the frequency of administration, depend on the desired effect, the potency and duration of action of the compounds used; additionally also on the nature and severity of the disorder to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated. In general, the doctor will determine the appropriate dosage as a function of the age and weight and all the other factors specific to the individual to be treated.

[0195] On average, the daily dose of a compound of the formula I and/or the pharmaceutically acceptable salts thereof for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 1 mg/kg, to a maximum of 1000 mg/kg, preferably 100 mg/kg, of body weight. For acute episodes of the disorder, for example immediately after suffering a myocardial infarction, higher and, in particular, more frequent dosages may also be necessary, e.g. up to 4 single doses a day. Up to 2000 mg a day may be necessary, in particular on i.v. administration, for example for a patient with infarction in the intensive care unit, and the compounds of the invention can be administered by infusion.

[0196] The following examples illustrate compositions according to the invention:

EXAMPLE A

[0197] Gel capsules containing a 50 mg dose of active product, having the composition below, can be prepared according to the usual technique: Compound of the formula (I) 50 mg Cellulose 18 mg Lactose 55 mg Colloidal silica  1 mg Sodium carboxymethyl starch 10 mg Talc 10 mg Magnesium stearate  1 mg

EXAMPLE B

[0198] Tablets comprising a 50 mg dose of active product, having the composition below, can be prepared according to the usual technique: Compound of the formula (I) 50 mg Lactose 104 mg  Cellulose 40 mg Polyvidone 10 mg Sodium carboxymethyl starch 22 mg Talc 10 mg Magnesium stearate  2 mg Colloidal silica  2 mg Mixture of hydroxymethylcellulose, glycerol and 245 mg  titanium oxide (72/3.5/24.5) qs 1 finished film-coated tablet weighing

EXAMPLE C

[0199] An injectable solution comprising 10 mg of active product, having the composition below, can be prepared: Compound of the formula (I)   10 mg Benzoic acid   80 mg Benzyl alcohol 0.06 ml Sodium benzoate   80 mg 95% ethanol  0.4 ml Sodium hydroxide   24 mg Propylene glycol  1.6 ml Water qs   4 ml 

What is claimed is:
 1. A compound of the formula (I)

wherein, R1 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, R2 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH, R3 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH, Ar is a 9- or a 10-membered bicyclic heteroaryl having one, two or three nitrogen atoms, which may be linked via any of its positions and which is substituted in at least one of its positions by alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, nitro, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O)_(n)R4, CO₂H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO₃H, n=0, 1 or 2, Ra and Rb are independently of each other hydrogen, linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which may optionally contain another hetero atom chosen from O, S and N, R4 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH₂, or a racemic mixture, enantiomer, diastereomer, or tautomer of such compound, or a mixture thereof, or a pharmaceutically acceptable salt of such compound, racemic mixture, enantiomer, diastereomer, tautomer, or mixture.
 2. A compound according to claim 1 wherein: R1 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, R2 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH, R3 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH, Ar is quinoline, isoquinoline, quinazoline or 7H-pyrrolo-[2,3-d]-pyrimidine, which may be linked via any of its positions and which is substituted in at least one of its positions by alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, nitro, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O)_(n)R4, CO₂H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO₃H, n=0, 1 or 2, Ra and Rb are independently of each other hydrogen, linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which may optionally contain another hetero atom chosen from O, S and N, R4 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH₂.
 3. A compound according to claim 1 wherein: R1 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, R2 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH, R3 is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms or OH, Ar is 4-quinolinyl, 4-quinazolinyl or 4-(7H-pyrrolo-[2,3-d]-pyrimidinyl), which is substituted in at least one of its positions by alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, halogen, nitro, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, hydroxyl, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, S(O)_(n)R4, CO₂H, alkoxycarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylcarbonyl having 1, 2, 3, 4, 5 or 6 carbon atoms, CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO₃H, n=0, 1or 2, Ra and Rb are independent of each other hydrogen, linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which may optionally contain another hetero atom chosen from O, S and N, R4 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkylamino having 1, 2, 3, 4, 5 or 6 carbon atoms or NH_(2.)
 4. A compound according to claim 1 which is 3-Guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(2-methylquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(6-chloroquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(7-chloroquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(8-chloroquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(6-fluoroquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(8-fluoroquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(6,8-difluoroquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(6-fluoro-2-methylquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(7-fluoro-2-methylquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(8-fluoro-2-methylquinol-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole, 3-Guanidinocarbonyl-1-(7-chloroquinol-4-yl)-5-methoxy-2-methyl-1H-indole, 3-Guanidinocarbonyl-1-(6-fluoroquinol-4-yl)-5-methoxy-2-methyl-1H-indole, or 3-Guanidinocarbonyl-1-(6-chloro-quinazolin-4-yl)-5-methoxy-2-methyl-1H-indole, or a tautomer thereof or a pharmaceutically acceptable salt of such compound or tautomer.
 5. A pharmaceutical composition for human, veterinary, or phytoprotective use comprising a pharmaceutically effective amount of a compound according to claim 1 together with a pharmaceutically acceptable medium.
 6. A pharmaceutical composition for human, veterinary, or phytoprotective use comprising a pharmaceutically effective amount of a compound according to claim 1 together with a pharmaceutically acceptable medium in combination with a pharmaceutically effective amount of another pharmacologically active ingredient or medicament.
 7. A method for the treatment or prophylaxis of cardiovascular disease, metabolic disease, cancerous disease, or fibrotic disease comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound according to claim
 1. 8. A method for the treatment or prophylaxis of acute or chronic damage to, or disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events; arrhythmias, life-threatening cardiac ventricular fibrillation, myocardial infarction, angina pectoris; ischemic states of the heart, ischemic states of the peripheral and central nervous system, stroke, cerebral oedema attack, ischemic states of peripheral organs and tissues; states of shock; diseases in which cellular proliferation represents a primary or secondary cause; cancer, metastasis, prostate hypertrophy, prostate hyperplasia; atherosclerosis, disturbances of lipid metabolism, high blood pressure; disorders of the central nervous system; non-insulin-dependent diabetes mellitus, late damage from diabetes; thromboses, disorders resulting from endothelial dysfunction, intermittent claudication; fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels,.fibrotic disorders of lung, fibrotic disorders of the heart; heart failure, congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa; malaria, or coccidiosis in poultry, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound according to claim
 1. 9. A method according to claim 8 for the treatment or prophylaxis of allergic shock, cardiogenic shock, hypovolaemic shock or bacterial shock.
 10. A method according to claim 8 for the treatment or prophylaxis of essential hypertension.
 11. A method according to claim 8 for the treatment or prophylaxis of disorders resulting from overexcitability of the CNS.
 12. A method according to claim 11, for the treatment or prophylaxis of epilepsy or centrally induced convulsions.
 13. A method according to claim 8 for the treatment or prophylaxis of anxiety states, depressions or psychoses.
 14. A method for protecting an organ in a transplant donor during organ transplantation, both before and during the removal of the organ, comprising administering to said donor, a pharmaceutically effective amount of a compound according to claim
 1. 15. A method for protecting a removed organ during treatment with, or storage in physiological bath liquids, comprising contacting said organ with a compound according to claim
 1. 16. A method for protecting a removed organ during transfer to a recipient organism during organ transplantation, comprising contacting said organ with a compound according to claim
 1. 17. A method for preventing age-related tissue change, in a patient in need thereof, comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim
 1. 18. A method for prolonging life in a patient in need thereof, comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim
 1. 19. A method for the treatment or reduction of the cardiotoxic effects in thyrotoxicosis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 1. 20. A diagnostic agent comprising a compound according to claim
 1. 21. A method for the treatment or prophylaxis of acute or chronic damage to, or disorders or indirect sequelae of organs and tissues caused by ischemic or reperfusion events; arrhythmias, life-threatening cardiac ventricular fibrillation, myocardial infarction, angina pectoris; ischemic states of the heart, ischemic states of the peripheral and central nervous system, stroke, cerebral oedema attack, ischemic states of peripheral organs and tissues; states of shock; diseases in which cellular proliferation represents a primary or secondary cause; cancer, metastasis, prostate hypertrophy, prostate hyperplasia; atherosclerosis, disturbances of lipid metabolism, high blood pressure; disorders of the central nervous system; non-insulin-dependent diabetes mellitus, late damage from diabetes; thromboses, disorders resulting from endothelial dysfunction, intermittent claudication; fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels, fibrotic disorders of lung, fibrotic disorders of the heart; heart failure, congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa; malaria, or coccidiosis in poultry, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound according to claim 1, in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 22. A method according to claim 21 for the treatment or prophylaxis of allergic shock, cardiogenic shock, hypovolaemic shock or bacterial shock.
 23. A method according to claim 21 for the treatment or prophylaxis of essential hypertension.
 24. A method according to claim 21 for the treatment or prophylaxis of disorders resulting from overexcitability of the CNS.
 25. A method according to claim 24, for the treatment or prophylaxis of epilepsy or centrally induced convulsions.
 26. A method according to claim 21 for the treatment or prophylaxis of anxiety states, depressions or psychoses.
 27. A method for protecting an organ in a transplant donor during organ transplantation, both before and during the removal of the organ, comprising administering to said donor, a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 28. A method for protecting a removed organ during treatment with, or storage in physiological bath liquids, comprising contacting said organ with a compound according to claim 1 in combination with another medicament or active ingredient.
 29. A method for protecting a removed organ during transfer to a recipient organism during organ transplantation, comprising contacting said organ with a compound according to claim 1 in combination with another medicament or active ingredient.
 30. A method for preventing age-related tissue change, in a patient in need thereof, comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 31. A method for prolonging life in a patient in need thereof, comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 32. A method for the treatment or reduction of the cardiotoxic effects in thyrotoxicosis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 33. A diagnostic agent comprising a compound according to claim 1 in combination with an another medicament or active ingredient.
 34. A method of reducing the cardiotoxic or cytotoxic effects of cardiotoxic or cytotoxic medicaments or active ingredients having cardiotoxic or cytotoxic properties, in a patient in need thereof, comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of said cardiotoxic or cytotoxic medicament or active ingredient.
 35. A method for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs or tissues caused by ischemic or reperfusion events in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 1. 36. A method for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs or tissues caused by ischemic or reperfusion events in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 37. A method for the treatment of life-threatening cardiac ventricular fibrillation, in a patient in need thereof, comprising comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim
 1. 38. A method for the treatment of life-threatening cardiac ventricular fibrillation, in a patient in need thereof, comprising comprising administering to said patient, a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 39. A method for the treatment or prophylaxis of metastasis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 1. 40. A method for the treatment or prophylaxis of metastasis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 41. A method for the treatment or prophylaxis of fibrotic disorders of the heart, heart failure, or congestive heart failure, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 1. 42. A method for the treatment or prophylaxis of fibrotic disorders of the heart, heart failure, or congestive heart failure, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 43. A method for the treatment or prophylaxis of a disease which is related to NHE, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 1. 44. A method for the treatment or prophylaxis of a disease which is related to NHE, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 in combination with an effective amount of another medicament or active ingredient.
 45. A method for the treatment or prophylaxis of a disease which is related to NHE1, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 1. 46. A method for the treatment or prophylaxis of a disease which is related to NHE1, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 in combination with a pharmaceutically effective amount of another medicament or active ingredient.
 47. A method for protecting the organs or blood vessels during surgical intervention, in a patient in need thereof, comprising administering to such patient a pharmaceutically effective amount of a compound according to claim
 1. 48. A process for the preparation of a compound according to claim 1, comprising

a) reacting a heteroaryl halide ArX of the formula (VI) with a 3-alkoxycarbonyl-1H-indole of the formula (II); b) saponifying the obtained 3-alkoxycarbonyl-1-heteroaryl-indole of the formula (III); c) converting the obtained 3-carboxy-1-heteroaryl-indole of the formula (IV) to the corresponding acid chloride of the formula (V); d) reacting the acid chloride of formula (V) with guanidine, and isolating the compound according to claim 1; and optionally converting it into a pharmaceutically acceptable salt thereof, wherein in the compounds of the formula II, III, IV, V and VI Ar and R1 to R3 are defined as in claim 1, X is F, Cl, Br or I and R is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. 